Eupatilin

Korean J Physiol Pharmacol. 2014 Oct;18(5):383-90.

The effects of eupatilin (stillen®) on motility of human lower gastrointestinal tracts.[Pubmed: 25352757]

Gastrointestinal motility consists of phasic slow-wave contractions and the migrating motor complex (MMC). Eupatilin (Stillen®) has been widely used to treat gastritis and peptic ulcers, and various cytokines and neuropeptides are thought to be involved, which can affect gastrointestinal motility.
METHODS AND RESULTS:
We performed a study to identify the effects of Eupatilin on lower gastrointestinal motility with electromechanical recordings of smooth muscles in the human ileum and colon. Ileum and colon samples were obtained from patients undergoing bowel resection. The tissues were immediately stored in oxygenated Krebs-Ringer's bicarbonate solution, and conventional microelectrode recordings from muscle cells and tension recordings from muscle strips and ileal or colonic segments were performed. Eupatilin was perfused into the tissue chamber, and changes in membrane potentials and contractions were measured. Hyperpolarization of resting membrane potential (RMP) was observed after administration of Eupatilin. The amplitude, AUC, and frequency of tension recordings from circular and longitudinal smooth muscle strips and bowel segments of the ileum and colon were significantly decreased after admission of Eupatilin. Eupatilin elicited dose-dependent decreases during segmental tension recordings.
CONCLUSIONS:
In conclusion, Eupatilin (Stillen®) showed inhibitory effects on the human ileum and colon. We propose that this drug may be useful for treating diseases that increase bowel motility, but further studies are necessary.

Tumour Biol. 2013 Apr;34(2):875-85.

Inhibitory effects of eupatilin on tumor invasion of human gastric cancer MKN-1 cells.[Pubmed: 23292941]

Extracts of the whole herb of Artemisia asiatica Nakai (Asteraceae) are used in traditional oriental medicine to treat inflammation. Eupatilin (5,7-dihydroxy-3',4',6-trimethoxyflavone) is one of the pharmacologically active components found in A. asiatica, and has been shown to possess anti-tumoral effects in some malignancies, including gastric cancer. However, its anti-metastatic effect in gastric cancer is hardly known.
METHODS AND RESULTS:
In this study, anti-metastatic effect of Eupatilin was investigated in the human gastric cancer cell line, MKN-1. Eupatilin inhibited MKN-1 growth in a dose- and a time-dependent manner, and induced apoptosis with a concomitant increase of caspase-3 activity. ELISA demonstrated that release of pro-inflammatory cytokines (IL-1β, TNF-α, IL-6, and IL-8) was significantly reduced by Eupatilin. And p-AKT and p-ERK (p44/42) was reduced. Expression level of β-catenin and integrin was reduced and p-GSKβ was increased. In transcription reporter system, the activity of the transcriptional factor, NF-κB, was reduced by Eupatilin and the expression of p65 was down-regulated when MKN-1 cells were treated with Eupatilin. Moreover, a zymography study revealed that this reduction in invasive potential resulted from a reduction in type IV collagenolytic (gelatinolytic) activity. The expressions of metalloproteinases (MMP-2 and MMP-9) were also reduced in MKN-1 cells treated with Eupatilin. In vitro invasion assay, Eupatilin inhibited MKN-1 penetrating reconstituted basement membrane barriers.
CONCLUSIONS:
These results suggest that Eupatilin inhibits the MKN-1 gastric cancer cell proliferation via activation of caspase-3 and the metastatic potential of gastric cancer cells via down-regulation of NF-κB activity followed by reduction of pro-inflammatory cytokine-mediated MMPs expressions.

Biochem Biophys Res Commun . 2018 Feb 5;496(2):508-514.

Eupatilin, an activator of PPARα, inhibits the development of oxazolone-induced atopic dermatitis symptoms in Balb/c mice[Pubmed: 29353040]

Abstract Eupatilin (5,7-dihydroxy-3',4',6-trimethoxyflavone) is the main lipophilic flavonoid obtained from the Artemisia species. Eupatilin has been reported to have anti-apoptotic, anti-oxidative and anti-inflammatory activities. Previously, we found that Eupatilin increases transcriptional activity and expression of peroxisome proliferator-activated receptor α (PPARα) in a keratinocyte cell line and acts as an agonist of PPARα. PPARα agonists ameliorate atopic dermatitis (AD) and restore the skin barrier function. In this study, we confirmed that the effects of Eupatilin improved AD-like symptoms in an oxazolone-induced AD-like mouse model. Furthermore, we found that Eupatilin suppressed the levels of serum immunoglobulin E (IgE), interleukin-4 (IL-4), and AD involved cytokines, such as tumor necrosis factor α (TNFα), interferon-γ (IFN-γ), IL-1β, and thymic stromal lymphopoietin (TSLP), IL-33, IL-25 and increased the levels of filaggrin and loricrin in the oxazolone-induced AD-like mouse model. Taken together, our data suggest that Eupatilin is a potential candidate for the treatment of AD. Keywords: Atopic dermatitis; Eupatilin; IL-4; PPARα.

Biochem Biophys Res Commun . 2017 Nov 4;493(1):220-226.

Eupatilin with PPARα agonistic effects inhibits TNFα-induced MMP signaling in HaCaT cells[Pubmed: 28899779]

Abstract Eupatilin (5,7-dihydroxy-3,4,6-trimethoxyflavone) is a flavonoid compound exhibiting several beneficial biological activities, including neuroprotection, anti-cancer, antinociception, chondroprotection, anti-oxidation, and anti-inflammation. Our previous study demonstrated that Eupatilin specifically activates peroxisome proliferator-activated receptor alpha (PPARα) through direct binding. The PPAR subfamily includes ligand-dependent transcription factors that consist of three isotypes: PPARα, PPARβ/δ, and PPARγ. All isotypes are involved in inflammation, epidermal proliferation/differentiation and skin barrier function. Among them, PPARα regulates lipid and glucose metabolism and skin homeostasis. In this study, we confirm that the ability of Eupatilin as a PPARα activator significantly inhibited tumor necrosis factor-alpha (TNFα)-induced matrix metalloproteinase (MMP)-2/-9 expression and proteolytic activity in HaCaT human epidermal keratinocytes. Furthermore, we found that Eupatilin subsequently suppressed IκBα phosphorylation, blocked NF-κB p65 nuclear translocation and down-regulated MAPK/AP-1 signaling via PPARα activation. Taken together, our data suggest that Eupatilin inhibits TNFα-induced MMP-2/-9 expression by suppressing NF-κB and MAPK⁄AP-1 pathways via PPARα. Our findings suggest the usefulness of Eupatilin for preventing skin aging.

Biomed Pharmacother . 2017 Jan;85:136-140.

Eupatilin prevents H 2 O 2-induced oxidative stress and apoptosis in human retinal pigment epithelial cells[Pubmed: 27930977]

Abstract Eupatilin, a pharmacologically active flavone derived from the Artemisia plant species, is known to possess anti-oxidant activity. However, the effects of Eupatilin on oxidative stress-induced retinal damage in retinal pigment epithelium (RPE) cells and the potential mechanisms involved have not been explored. Therefore, the aim of this study was to investigate the effects of Eupatilin on oxidative stress-induced retinal damage in RPE cells. Our results showed that Eupatilin significantly attenuated H2O2-induced cell injury and ROS production in ARPE-19 cells. In addition, Eupatilin pretreatment greatly upregulated Bcl-2 expression, downregulated Bax expression, as well as suppressed caspase-3 activity in ARPE-19 cells exposed to H2O2. Furthermore, Eupatilin pretreatment markedly enhanced phosphorylation levels of PI3K and Akt in ARPE-19 cells exposed to H2O2. In conclusion, our data showed that Eupatilin protected against H2O2-induced oxidative stress and apoptosis through the activation of PI3K/Akt signaling pathway in ARPE-19 cells. Thus, Eupatilin may be useful for the prevention or treatment of proliferative vitreoretinopathy (PVR). Keywords: Apoptosis; Eupatilin; Oxidative stress; Retinal pigment epithelium (RPE).

J Korean Med Sci. 2015 Mar;30(3):233-9.

Eupatilin ameliorates collagen induced arthritis.[Pubmed: 25729243]

Eupatilin is the main active component of DA-9601, an extract from Artemisia. Recently, Eupatilin was reported to have anti-inflammatory properties. We investigated the anti-arthritic effect of Eupatilin in a murine arthritis model and human rheumatoid synoviocytes.
METHODS AND RESULTS:
DA-9601 was injected into collagen-induced arthritis (CIA) mice. Arthritis score was regularly evaluated. Mouse monocytes were differentiated into osteoclasts when Eupatilin was added simultaneously. Osteoclasts were stained with tartrate-resistant acid phosphatase and then manually counted. Rheumatoid synoviocytes were stimulated with TNF-α and then treated with Eupatilin, and the levels of IL-6 and IL-1β mRNA expression in synoviocytes were measured by RT-PCR. Intraperitoneal injection of DA-9601 reduced arthritis scores in CIA mice. TNF-α treatment of synoviocytes increased the expression of IL-6 and IL-1β mRNAs, which was inhibited by Eupatilin. Eupatilin decreased the number of osteoclasts in a concentration dependent manner.
CONCLUSIONS:
These findings, showing that Eupatilin and DA-9601 inhibited the expression of inflammatory cytokines and the differentiation of osteoclasts, suggest that Eupatilin and DA-9601 is a candidate anti-inflammatory agent.

Scand J Immunol. 2015 Mar;81(3):166-76.

The flavone eupatilin inhibits eotaxin expression in an NF-κB-dependent and STAT6-independent manner.[Pubmed: 25565108]

The CC chemokine eotaxin contributes to epithelium-induced inflammation in airway diseases such as asthma. Eupatilin (5,7-dihydroxy-3',4',6'-trimethoxyflavone), a bioactive component of Artemisia asiatica Nakai (Asteraceae), is reported to inhibit the adhesion of eosinophils to bronchial epithelial cells. However, little is known about the molecular mechanism of Eupatilin-induced attenuation of bronchial epithelium-induced inflammation.
METHODS AND RESULTS:
In this study, we investigated the effect of Eupatilin on expression of eotaxin-1 (CCL11), a potent chemoattractant for eosinophils. Eupatilin significantly inhibited eotaxin expression in bronchial epithelial cells stimulated with TNF-α, while NF-κB and IκBα kinase (IKK) activities declined concurrently. Eupatilin also inhibited mitogen-activated protein kinase (MAPK) activity; however, all of these anti-inflammatory activities were reversed by MAPK overexpression. In contrast, Eupatilin did not affect the signal transducer and activator of transcription 6 (STAT6) signalling in bronchial epithelial cells stimulated with IL-4. Furthermore, Eupatilin significantly attenuated TNF-α-induced eosinophil migration.
CONCLUSIONS:
These results suggest that the Eupatilin inhibits the signalling of MAPK, IKK, NF-κB and eotaxin-1 in bronchial epithelial cells, leading to inhibition of eosinophil migration.

Transplant Proc. 2015 Apr;47(3):757-62.

Protective effect of eupatilin against renal ischemia-reperfusion injury in mice.[Pubmed: 25891726]

Eupatilin, a pharmacologically active flavone derived from Artemisia species, is known to have antioxidant and anti-inflammatory activities. Ischemia-reperfusion injury (IRI) is a major complication after renal transplantation, with inflammatory responses to IRI exacerbating the resultant renal injury. In the present study, we investigated whether Eupatilin exhibits renoprotective activities against ischemia-reperfusion-induced acute kidney injury in mice.
METHODS AND RESULTS:
Renal IRI was induced in male C57BL/6 mice by bilateral renal pedicle occlusion for 30 minutes followed by reperfusion for 48 hours. Eupatilin (10 mg/kg body weight p.o.) was administered 4 days before IRI. Treatment with Eupatilin significantly decreased neutrophil gelatinase-associated lipocalin and kidney injury molecule-1 levels in urine, blood urea nitrogen level, and serum creatinine levels, as well as kidney tubular injury. Western blotting indicated that Eupatilin significantly increased the levels of heat shock protein 70 and B-cell lymphoma protein, and it attenuated inducible nitric oxide synthase, Bcl-2-associated X protein, and caspase-3 levels 48 hours after IRI.
CONCLUSIONS:
Our findings suggest that Eupatilin is a promising therapeutic agent against acute ischemia-induced renal damage.